WO2015019030A1 - Novel combination of 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl}oxy)-n-methylnaphthalene-1-carboxamide and an anti-oestrogen in breast cancer - Google Patents
Novel combination of 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl}oxy)-n-methylnaphthalene-1-carboxamide and an anti-oestrogen in breast cancer Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- the present invention relates to a novel combination of 6 - ( ⁇ 7 - [(1-acetopolypyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene-1-carboxamide of formula (I):
- 6- ( ⁇ 7 - [(1-Aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methyl naphthalene-1-carboxamide is a potent inhibitor of angiogenesis described in WO patent application 2008/1 12408. More specifically, the compound of formula (I) selectively inhibits the activity of FGF receptors type 1 and 2 (FGFR1 and FGFR2), that of alpha and beta type PDGF receptors (PDGFR ⁇ and PDGFRp), and that of type 1, 2 and 3 VEGF receptors (VEGFR1, VEGFR2 and VEGFR3).
- the present invention relates to the combination of 6 - ( ⁇ 7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene-1-carboxamide of formula (I) or its salts addition to a pharmaceutically acceptable acid or base, and an antiestrogen, as well as its properties for the treatment of breast cancer, more particularly, for the treatment of ER + / HER2- metastatic breast cancer and, more particularly , in patients resistant to hormone therapy.
- ER + / HER2- breast cancer HER2-overexpressing breast cancer
- triple-negative breast cancer The ER + / HER2- phenotype is the most common and accounts for about 70% of all breast cancers.
- Hormone therapy is the standard treatment for ER + / HER2- breast cancer (Cardoso et al., Breast 2012, 21 (3), 242-52).
- the invention also covers the use of 6 - ( ⁇ 7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene-1-carboxamide in combination with a anti-estrogen for the treatment of breast cancer, more particularly for the treatment of ER + / HER2- metastatic breast cancer and, more particularly, in patients resistant to hormone therapy.
- 6 - ( ⁇ 7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene-1-carboxamide is used in free base form.
- 6 - ( ⁇ 7 - [(1-Aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methyl naphthalene-1-carboxamide may also be used in the form of a hydrochloride.
- antiestrogen used is a selective estrogen receptor modulator (or SERM) and, preferably, tamoxifen.
- SERM selective estrogen receptor modulator
- Another preferred embodiment is to use as an anti-estrogen a selective negative estrogen receptor (or SERD) regulator and, preferably, fulvestrant.
- SERM selective estrogen receptor modulator
- SERD selective negative estrogen receptor
- 6 - ( ⁇ 7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene-1-carboxamide is used in combination with fulvestrant.
- the invention also relates to pharmaceutical compositions containing the combination of 6 - ( ⁇ 7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methyl-naphthalene-1-carboxamide or its addition salts with a pharmaceutically acceptable acid or base, and an antiestrogen in combination with one or more pharmaceutically acceptable excipients.
- the invention also relates to the use of said pharmaceutical compositions in the treatment of breast cancer, more particularly for the treatment of ER + / HER2- metastatic breast cancer and, more particularly, in patients resistant to hormone therapy.
- the mass fraction of active principles is between 3 and 50%.
- compositions according to the invention more particularly those suitable for oral, parenteral, intramuscular and intravenous, percutaneous, transcutaneous, nasal, rectal, perlingual, ocular, respiratory administration and more specifically single or coated tablets, sublingual tablets, capsules, glossettes, capsules, tablets, injectables, aerosols, eye or nasal drops, suppositories, creams, ointments, skin gels, etc.
- 6 - ( ⁇ 7 - [(1-aminocyclopi pyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene-1-carboxamide is administered orally.
- the pharmaceutical compositions according to the invention contain one or more excipients or carriers selected from diluents, lubricants, binders, disintegrating agents, stabilizers, preservatives, absorbents, colorants, sweeteners, flavorings, etc.
- lactose lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerine;
- binders magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone;
- agar for disintegrators: agar, alginic acid and its sodium salt, effervescent mixtures.
- the compounds of the combination can be administered simultaneously or sequentially.
- the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients.
- the compounds of the combination may be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or else in the form of form of a single pharmaceutical composition, in which the active ingredients are mixed.
- the appropriate dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the cancer and any associated treatments, and ranges from 1 to 30 mg of 6 - ( ⁇ 7- [ (1-Aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methyl-naphthalene-1-carboxamide per day and, more preferably, 5, 10 or 15 mg per day.
- the dose of the anti-estrogen will be equal to that used when administered alone. In the case of fulvestrant, the dose administered monthly is 500 mg. In the case of tamoxifen, the dosage is 20 mg per day.
- the cells are distributed in 96-well plates (90 to 15,000 cells per well). After 48 to 72 hours of culture, the cells are exposed to 6 - ( ⁇ 7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methyl naphthalene-1-carboxamide, 4-OHT or fulvestrant, alone or in combination for 96 to 168 hours over concentrations ranging from 1 nmol / L to 100 ⁇ / L, in the presence or absence of FGF2 ( fibroblast growth type 2). Cell viability is then quantified by a colorimetric assay, Tetrazolium Assay Micro Culture (Carmichael et al., Cancer Res., 1987, 47, 936-942).
- fulvestrant In the absence of FGF2, fulvestrant (0.1 ⁇ / L) inhibits by more than 50% the proliferation of cells of the SUM44PE (ER + / HER2- breast carcinoma), amplified for the FGFR1 gene.
- fulvestrant In the presence of 50 ng / mL FGF2, fulvestrant has no effect on this proliferation. This result suggests that activation of the FGFR / FGF signaling pathway is involved in fulvestrant resistance, in the case of amplification of the FGFRL gene.
- the study consists of 28-day cycles in the following manner: 6 - ( ⁇ 7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene 1 -carboxamide is administered orally daily from the 15th day of the 1st cycle.
- patients receive an intramuscular injection of fulvestrant the I day of each cycle.
- An additional dose of fulvestrant is administered on day 15 of cycle 1 only in patients who have not received fulvestrant or whose last dose was more than two months before study entry.
- the maximum number of cycles is at the discretion of the investigator.
- the daily dose of 6 - ( ⁇ 7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl ⁇ oxy) -N-methylnaphthalene-1-carboxamide is 5, 10 or 15 mg at 2 hours distance a meal. Fulvestrant is given at a dose of 500 mg (as two 250 mg injections).
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Abstract
Description
NOUVELLE ASSOCIATION ENTRE LE NEW ASSOCIATION BETWEEN THE
6-{{7-[(l-AMINOCYCLOPROPYL)METHOXY]~6-METHOXY QUINOLEIN-4-YL}OXY)- V-METHYLNAPHT ALENE- 1-CARBOXAMIDE 6 - {{7 - [(1-AMINOCYCLOPROPYL) METHOXY] -6-METHOXY QUINOLIN-4-YL} OXY) -V-METHYLNAPHT ALENE-1-CARBOXAMIDE
ET UN ANTI-ŒSTROGENE DANS LE CANCER DU SEIN AND AN ANTI-ESTROGEN IN BREAST CANCER
La présente invention concerne une nouvelle association entre le 6-({7-[(l-araino cyclopi pyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N-méthylnaphtalène-l-carboxamide de formule (I) : The present invention relates to a novel combination of 6 - ({7 - [(1-acetopolypyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide of formula (I):
Le 6-( {7-[(l -aminocyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl} oxy)-N-méthyl naphtalène-l -carboxamide est un inhibiteur puissant de l'angiogenèse décrit dans la demande de brevet WO 2008/1 12408. Plus précisément, le composé de formule (I) inhibe sélectivement l'activité des récepteurs à FGF de type 1 et 2 (FGFR1 et FGFR2), celle des récepteurs PDGF de type alpha et beta (PDGFRa et PDGFRp), et celle des récepteurs à VEGF de type 1 , 2 et 3 (VEGFR1 , VEGFR2 et VEGFR3). Il démontre une activité antiproliférative dans plusieurs lignées de cellules cancéreuses cultivées in vitro et inhibe la croissance tumorale in vivo dans des modèles de xénogreffes (Bello et al. Cancer Res. 2011, 71(4), 1396-405). Son profil pharmacologique lui confère un intérêt thérapeutique majeur dans le traitement du cancer. 6- ({7 - [(1-Aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methyl naphthalene-1-carboxamide is a potent inhibitor of angiogenesis described in WO patent application 2008/1 12408. More specifically, the compound of formula (I) selectively inhibits the activity of FGF receptors type 1 and 2 (FGFR1 and FGFR2), that of alpha and beta type PDGF receptors (PDGFRα and PDGFRp), and that of type 1, 2 and 3 VEGF receptors (VEGFR1, VEGFR2 and VEGFR3). It demonstrates antiproliferative activity in several tumor cell lines cultured in vitro and inhibits tumor growth in vivo in xenograft models (Bello et al., Cancer Res 2011, 71 (4), 1396-405). Its pharmacological profile gives it a major therapeutic interest in the treatment of cancer.
La présente invention concerne l'association entre le 6-({7-[(l -aminocyclopropyI) méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N-méthylnaphtalène- l -carboxamide de formule (I) ou ses sels d'addition à un acide ou à une base phannaceutiquement acceptable, et un anti-œstrogène, ainsi que ses propriétés pour le traitement du cancer du sein, plus particulièrement, pour le traitement du cancer du sein métastatique ER+/HER2- et, plus particulièrement, chez les patientes résistantes à une hormonothérapie. Le cancer du sein métastatique demeure incurable avec environ 41 000 décès par an associés à la maladie aux États-Unis (Jemal et al. Cancer J, Clin. 2008, 58, 71-96) et 131 000 décès par an en Europe (Ferlay et al. Eut. J Cancer 2013, 49(6), 1374-403). Le cancer du sein comprend trois principales classes moléculaires : le cancer du sein ER+/HER2-, le cancer du sein surexprimant HER2 et le cancer du sein triple négatif. Le phénotype ER+/HER2- est le plus fréquent et représente environ 70 % de tous les cancers du sein. L'hormonothérapie est le traitement de référence du cancer du sein ER+/HER2- (Cardoso et al. Breast 2012, 21(3), 242-52). Malheureusement, on observe que la plupart des patientes rechuteront après plusieurs mois de traitement et, une fois le cancer du sein devenu hormonorésistant, le pronostic devient très faible et les patientes se voient proposer une chimiothérapie dont l'utilité repose sur trop peu de données cliniques. Dans ce contexte, la recherche de nouvelles alternatives thérapeutiques dans le cancer du sein métastatique ER+/HER2- et, particulièrement, chez les patientes hormonorésistantes, en vue d'améliorer la survie sans progression, reste toujours d'actualité. En particulier, resensibiliser les patientes résistantes aux hormonothérapies déjà validées cliniquement constitue une stratégie thérapeutique à explorer. The present invention relates to the combination of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide of formula (I) or its salts addition to a pharmaceutically acceptable acid or base, and an antiestrogen, as well as its properties for the treatment of breast cancer, more particularly, for the treatment of ER + / HER2- metastatic breast cancer and, more particularly , in patients resistant to hormone therapy. Metastatic breast cancer remains incurable with approximately 41,000 deaths per year associated with the disease in the United States (Jemal et al., Cancer Clinic 2008, 58, 71-96) and 131,000 deaths per year in Europe (Ferlay et al., J Cancer 2013, 49 (6), 1374-403). Breast cancer has three main molecular classes: ER + / HER2- breast cancer, HER2-overexpressing breast cancer, and triple-negative breast cancer. The ER + / HER2- phenotype is the most common and accounts for about 70% of all breast cancers. Hormone therapy is the standard treatment for ER + / HER2- breast cancer (Cardoso et al., Breast 2012, 21 (3), 242-52). Unfortunately, it is observed that most patients will relapse after several months of treatment and, once breast cancer has become hormone-resistant, the prognosis becomes very low and patients are offered chemotherapy whose usefulness is based on too little clinical data. . In this context, the search for new therapeutic alternatives in ER + / HER2- metastatic breast cancer and, particularly, in hormone-resistant patients, to improve progression-free survival, is still relevant. In particular, resensitizing hormone-resistant patients already clinically validated is a therapeutic strategy to explore.
Selon l'invention, il a été montré que les effets du 6-({7-[(l-aminocyclopropyl)méthoxy]- 6-méthoxyquinoléin-4-yl}oxy)-N-méthylnaphtalène-l-carboxamide ou de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable permettaient d'inverser la résistance aux anti-œstrogènes chez les patientes préalablement traitées par cette hormono thérapie. According to the invention, it has been shown that the effects of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide or its salts addition to a pharmaceutically acceptable acid or base was effective in reversing antiestrogen resistance in patients previously treated with this hormone therapy.
Ces effets permettent d'envisager l'utilisation de l'association du 6-({7-[(l-amino cyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl} oxy)-N-méthylnaphtalène- 1 -carboxamide et d'un anti-œstrogène dans le traitement des cancers du sein traités en première ligne par une hormonothérapie chez des patientes pour lesquelles une progression de la maladie ou une rechute a été observée malgré le traitement hormonal. These effects make it possible to envisage the use of the combination of 6 - ({7 - [(1-amino cyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide and an anti-estrogen in the treatment of breast cancer treated in the first line with hormone therapy in patients for whom disease progression or relapse has been observed despite hormonal treatment.
L'invention couvre aussi l'utilisation du 6-({7-[(l -aminocyclopropyl)méthoxy]-6- méthoxyquinoléin-4-yl}oxy)-N-méthylnaphtalène-l -carboxamide en association avec un anti-œstrogène pour le traitement du cancer du sein, plus particulièrement, pour le traitement du cancer du sein métastatique ER+/HER2- et, plus particulièrement, chez les patientes résistantes à une hormonothérapie. The invention also covers the use of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide in combination with a anti-estrogen for the treatment of breast cancer, more particularly for the treatment of ER + / HER2- metastatic breast cancer and, more particularly, in patients resistant to hormone therapy.
Préférentiellement, le 6-({7-[(l -aminocyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl} oxy)-N-méthylnaphtalène-l -carboxamide est utilisé sous forme de base libre. Preferably, 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide is used in free base form.
Le 6-({7-[( l -aminocyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N-méthyl naphtalène-l -carboxamide peut être également utilisé sous forme d'un chlorhydrate. 6 - ({7 - [(1-Aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methyl naphthalene-1-carboxamide may also be used in the form of a hydrochloride.
Selon un mode de réalisation avantageux, anti-œstrogène utilisé est un modulateur sélectif des récepteurs aux œstrogènes (ou SERM) et, préférentiellement le tamoxifène. Un autre mode de réalisation préféré consiste à utiliser comme anti-œstrogène un régulateur négatif sélectif des récepteurs aux œstrogènes (ou SERD) et, préférentiellement le fulvestrant. According to an advantageous embodiment, antiestrogen used is a selective estrogen receptor modulator (or SERM) and, preferably, tamoxifen. Another preferred embodiment is to use as an anti-estrogen a selective negative estrogen receptor (or SERD) regulator and, preferably, fulvestrant.
De manière préférentielle, le 6-({7-[(l-aminocyclopropyI)méthoxy]-6-méthoxyquinoléin- 4-yl}oxy)-N-méthylnaphtalène-l-carboxamide est utilisé en association avec le fulvestrant. Preferably, 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide is used in combination with fulvestrant.
L'invention concerne également les compositions pharmaceutiques contenant l'association entre le 6-({7-[(l-aminocyclopiOpyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-iV-méthyl naphtalène-l -carboxamide ou ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, et un anti-œstrogène en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables. L'invention concerne aussi l'utilisation desdites compositions pharmaceutiques dans le traitement du cancer du sein, plus particulièrement, pour le traitement du cancer du sein métastatique ER+/HER2- et, plus particulièrement, chez les patientes résistantes à une hormonothérapie. The invention also relates to pharmaceutical compositions containing the combination of 6 - ({7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methyl-naphthalene-1-carboxamide or its addition salts with a pharmaceutically acceptable acid or base, and an antiestrogen in combination with one or more pharmaceutically acceptable excipients. The invention also relates to the use of said pharmaceutical compositions in the treatment of breast cancer, more particularly for the treatment of ER + / HER2- metastatic breast cancer and, more particularly, in patients resistant to hormone therapy.
Dans les compositions pharmaceutiques selon l'invention, la fraction massique en principes actifs (masse des principes actifs sur la masse totale de la composition) est comprise entre 3 et 50 %. In the pharmaceutical compositions according to the invention, the mass fraction of active principles (mass of the active ingredients on the total mass of the composition) is between 3 and 50%.
Parmi les compositions pharmaceutiques selon l'invention, on retiendra plus particulièrement celles qui conviennent pour Γ administration par voie orale, parentérale, intramusculaire et intraveineuse, per ou transcutanée, nasale, rectale, perlinguale, oculaire, respiratoire et plus spécifiquement les comprimés simples ou dragéifiés, les comprimés sublinguaux, les gélules, les glossettes, les capsules, les tablettes, les préparations injectables, les aérosols, les gouttes oculaires ou nasales, les suppositoires, les crèmes, pommades, gels dermiques, etc.. Among the pharmaceutical compositions according to the invention, more particularly those suitable for oral, parenteral, intramuscular and intravenous, percutaneous, transcutaneous, nasal, rectal, perlingual, ocular, respiratory administration and more specifically single or coated tablets, sublingual tablets, capsules, glossettes, capsules, tablets, injectables, aerosols, eye or nasal drops, suppositories, creams, ointments, skin gels, etc.
Dans un mode de réalisation préféré, le 6-({7-[(l-aminocyclopi pyl)méthoxy]-6-méthoxy quinoléin-4-yl}oxy)-N-méthylnaphtalène-l -carboxamide est administré sous forme orale. In a preferred embodiment, 6 - ({7 - [(1-aminocyclopi pyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide is administered orally.
Outre le 6-({7- (l-atiiinocyclopiOpyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N-métliyl naphtalène-l -carboxamide et l 'anti-œstrogène, les compositions pharmaceutiques selon l'invention contiennent un ou plusieurs excipients ou véhicules choisis parmi des diluants, des lubrifiants, des liants, des agents de désintégration, les stabilisants, les conservateurs, des absorbants, des colorants, des édulcorants, les aromatisants, etc.. In addition to 6 - ({7- (1-atiinocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methyl-naphthalene-1-carboxamide and the antiestrogen, the pharmaceutical compositions according to the invention contain one or more excipients or carriers selected from diluents, lubricants, binders, disintegrating agents, stabilizers, preservatives, absorbents, colorants, sweeteners, flavorings, etc.
A titre d'exemple et de manière non limitative, on peut citer : By way of example and in a nonlimiting manner, mention may be made of:
- pour les diluants : le lactose, le dextrose, le sucrose, le mannitol, le sorbitol, la cellulose, la glycérine ; - for diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerine;
- pour les lubrifiants ; la silice, le talc, l'acide stéarique et ses sels de magnésium et de calcium, le polyéthylène glycol ; - for lubricants; silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol;
- pour les liants : le silicate d'aluminium et de magnésium, l'amidon, la gélatine, la tragacanthe, la méthylcellulose, la carboxyméthylcellulose de sodium et la polyvinylpyrrolidone ; binders: magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone;
- pour les désintégrants : l'agar, l'acide alginique et son sel de sodium, les mélanges effervescents. - for disintegrators: agar, alginic acid and its sodium salt, effervescent mixtures.
Les composés de l'association peuvent être administrés de manière simultanée ou séquentielle. Les compositions pharmaceutiques correspondantes peuvent permettre la libération instantanée ou différée des principes actifs. Par ailleurs, les composés de l'association peuvent être administrés sous la forme de deux compositions pharmaceutiques distinctes, contenant chacune l'un des principes actifs, ou bien sous la forme d'une seule composition pharmaceutique, dans laquelle les principes actifs sont mélangés. The compounds of the combination can be administered simultaneously or sequentially. The corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients. Moreover, the compounds of the combination may be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or else in the form of form of a single pharmaceutical composition, in which the active ingredients are mixed.
La posologie utile varie selon le sexe, l'âge et le poids du patient, la voie d'administration, la nature du cancer et des traitements éventuellement associés, et s'échelonne entre 1 et 30 mg de 6-({7-[(l -aminocyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-jV-méthyl naphtalène-l-carboxamide par jour et, plus préférentiel lement, 5, 10 ou 15 mg par jour. La dose de l'anti-œstrogène sera égale à celle utilisée lorsqu'il est administré seul. Dans le cas du fulvestrant, la dose administrée mensuellement est de 500 mg. Dans le cas du tamoxifène, la posologie est de 20 mg par jour. The appropriate dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the cancer and any associated treatments, and ranges from 1 to 30 mg of 6 - ({7- [ (1-Aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methyl-naphthalene-1-carboxamide per day and, more preferably, 5, 10 or 15 mg per day. The dose of the anti-estrogen will be equal to that used when administered alone. In the case of fulvestrant, the dose administered monthly is 500 mg. In the case of tamoxifen, the dosage is 20 mg per day.
ETUDE PRECLINIQUE : PRECLINICAL STUDY:
Activité antiproliférative in vitro de l'association entre le 6-({7-[(l-aminocyclopropyl) méthoxy]-6-méthoxyquinolém-4-yI}oxy)-N-méthylnaphtalène-l-carboxamide et un anti-œstrogène In vitro antiproliferative activity of the combination of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinol-4-yl} oxy) -N-methylnaphthalene-1-carboxamide and an anti-estrogen
L'effet antiprolifératif du 6-({7-[(l-aminocyclopropyl)méthoxy]-6-méthoxyquinoIéin-4- yl}oxy)- V-méthylnaphtalène-l-carboxamide, seul ou en association avec le fulvestrant ou le 4-hydroxytamoxifène (ou 4-OHT ; métabolite actif du tamoxifène), est évalué dans 9 lignées de carcinome de sein humain (ER+/HER2-) : The antiproliferative effect of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide, alone or in combination with fulvestrant or 4- hydroxytamoxifene (or 4-OHT, active metabolite of tamoxifen), is evaluated in 9 human breast carcinoma lines (ER + / HER2-):
- 4 lignées amplifiées pour le gène FGFR1 : SUM44PE, MDA-MB-134-VI, CAMA-1 et MDA-MB-361 ; 4 amplified lines for the FGFR1 gene: SUM44PE, MDA-MB-134-VI, CAMA-1 and MDA-MB-361;
- 5 lignées non amplifiées pour le gène FGFR1 : MCF-7, ZR-75- 1 , ZR-75-30, T-47D et BT 474. 5 non-amplified lines for the FGFR1 gene: MCF-7, ZR-75-1, ZR-75-30, T-47D and BT 474.
Les cellules sont cultivées dans des milieux de culture à pH = 7,4 supplémentés en sérum de veau fœtal dans un incubateur à 37 °C en présence de 5 % de C02. The cells are cultured in culture media at pH = 7.4 supplemented with fetal calf serum in an incubator at 37 ° C in the presence of 5% CO 2 .
Pour le test de viabilité, les cellules sont réparties dans des plaques 96 puits (90 à 15 000 cellules par puits). Après 48 à 72 heures de culture, les cellules sont exposées au 6-({7-[(l-aminocyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-jV-méthyl naphtalène-l-carboxamide, au 4-OHT ou au fulvestrant, seuls ou en combinaison pendant 96 à 168 heures sur des gammes de concentrations allant de 1 nmol/L à 100 μηιοΙ/L, en présence ou en absence de FGF2 (facteur de croissance du fibroblaste de type 2). La viabilité cellulaire est ensuite quantifiée par un essai colorimétrique, le Micro culture Tetrazolium Assay (Carmichael et al. Cancer Res. 1987, 47, 936-942). For the viability test, the cells are distributed in 96-well plates (90 to 15,000 cells per well). After 48 to 72 hours of culture, the cells are exposed to 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methyl naphthalene-1-carboxamide, 4-OHT or fulvestrant, alone or in combination for 96 to 168 hours over concentrations ranging from 1 nmol / L to 100 μηιοΙ / L, in the presence or absence of FGF2 ( fibroblast growth type 2). Cell viability is then quantified by a colorimetric assay, Tetrazolium Assay Micro Culture (Carmichael et al., Cancer Res., 1987, 47, 936-942).
En absence de FGF2, le fulvestrant (0,1 μιηοΙ/L) inhibe à plus de 50 % la prolifération des cellules de la lignée SUM44PE (carcinome de sein ER+/HER2-), amplifiée pour le gène FGFR1. In the absence of FGF2, fulvestrant (0.1 μιηοΙ / L) inhibits by more than 50% the proliferation of cells of the SUM44PE (ER + / HER2- breast carcinoma), amplified for the FGFR1 gene.
En présence de 50 ng/mL de FGF2, le fulvestrant n'a plus d'effet sur cette prolifération. Ce résultat suggère que l'activation de la voie de signalisation FGFR/FGF est impliquée dans la résistance au fulvestrant, dans le cas d'une amplification du gène FGFRL In the presence of 50 ng / mL FGF2, fulvestrant has no effect on this proliferation. This result suggests that activation of the FGFR / FGF signaling pathway is involved in fulvestrant resistance, in the case of amplification of the FGFRL gene.
Le traitement combiné du 6-({7-[(l~arninocyclopropyl)méthoxy]-6-méthoxyquinoléin-4- yl}oxy)-N-méthylnaphtalène-l-carboxamide et du fulvestrant en présence de FGF2, dans les cellules SUM44PE, montre une levée de la résistance au fulvestrant à partir de la dose de 1 μιηοΙ/L de 6-({7-[(l-aminocyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N- méthylnaphtalène-l-carboxamide (Figure 1). The combined treatment of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide and fulvestrant in the presence of FGF2, in SUM44PE cells, shows a rise in fulvestrant resistance from the dose of 1 μιηοΙ / L of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1 carboxamide (Figure 1).
Par conséquent, l'effet antiprolifératif du 6-({7-[(î-aminocyclopiOpyl)méthoxy]-6- méthoxyquinoléin-4-yl}oxy)-N-méthylnaphtalène-l-carboxamide en association avec un anti-œstrogène est encourageant pour le traitement cancer du sein métastatique ER+/HER2-. Therefore, the antiproliferative effect of 6 - ({7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide in combination with an antiestrogen is encouraging. for ER + / HER2- metastatic breast cancer treatment.
ETUDE CLINIQUE CLINICAL STUDY
Une étude clinique de Phase Ib sur 46 patientes est réalisée pour tester l'association du 6-({7-[(l-aminocyclopiOpyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-jV-méthyl naphtalène-l-carboxamide avec le fulvestrant dans le traitement du cancer du sein métastatique ER+/HER2-. Les patientes reçoivent l'association tant que le traitement se révèle bénéfique (évaluation tumorale tous les deux cycles) et en l'absence de toxicité sérieuse. A Phase Ib clinical study in 46 patients was performed to test the combination of 6 - ({7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methyl-naphthalene. carboxamide with fulvestrant in the treatment of ER + / HER2- metastatic breast cancer. The patients receive the association as long as the treatment is reveals beneficial (tumor evaluation every two cycles) and in the absence of serious toxicity.
Plus précisément, l'étude consiste en cycles de 28 jours se déroulant de la manière suivante : le 6-({7-[(l -aminocyclopiOpyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N- méthylnaphtalène-1 -carboxamide est administré quotidiennement par voie orale à partir du 15e jour du 1er cycle. En outre, les patientes reçoivent une injection intramusculaire de fulvestrant le Ie jour de chaque cycle. Une dose supplémentaire de fulvestrant est administrée le 15e jour du 1 er cycle uniquement chez les patientes qui n'ont pas reçu de fulvestrant ou dont la dernière dose remonte à plus de deux mois avant l'entrée dans l'étude. Le nombre maximum de cycles est à la discrétion de l'investigateur. Specifically, the study consists of 28-day cycles in the following manner: 6 - ({7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene 1 -carboxamide is administered orally daily from the 15th day of the 1st cycle. In addition, patients receive an intramuscular injection of fulvestrant the I day of each cycle. An additional dose of fulvestrant is administered on day 15 of cycle 1 only in patients who have not received fulvestrant or whose last dose was more than two months before study entry. The maximum number of cycles is at the discretion of the investigator.
La dose journalière de 6-({7-[(l-aminocyclopiOpyl)méthoxy]-6-méthoxyquinoléin-4-yl} oxy)-jV-méthylnaphtalène-l-carboxamide est de 5, 10 ou 15 mg à 2 heures de distance d'un repas. Le fulvestrant est administré à la dose de 500 mg (sous la forme de deux injections de 250 mg). The daily dose of 6 - ({7 - [(1-aminocyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide is 5, 10 or 15 mg at 2 hours distance a meal. Fulvestrant is given at a dose of 500 mg (as two 250 mg injections).
Au 15e jour du 2e cycle de traitement, la toxicité de l'association entre le 6-({7-[(l-amino cyclopropy l)méthoxy] - 6-méthoxyquinoléin-4-yl } oxy)-N-méthylnaphtalène- 1 -carboxamide et le fulvestrant est évaluée. Si aucune toxicité rédhibitoire n'est observée, la patiente continue le traitement. On day 15 of the 2nd treatment cycle, the toxicity of the association between 6 - ({7 - [(l-cyclopropyl-l amino) methoxy] - 6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene 1-carboxamide and fulvestrant is evaluated. If no unacceptable toxicity is observed, the patient continues the treatment.
Tous les deux cycles de traitement, l'efficacité de l'association entre le 6-({7-[(l -amino cyclopiOpyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N-méthylnaphtalène-l -carboxamide et le fulvestrant est appréciée via l'évaluation de la réponse tumorale en utilisant le critère RECIST version 1.1 (CT-scan ou JRM). Le profil d'acceptabilité est également évalué (toxicités hématologiques, cardiaques, rénales et hépatiques). Un screening moléculaire est aussi effectué afin de déterminer les patientes atteintes d'un cancer du sein avec une amplification du gène FGFR1 et/ou des gènes CCND 1 /FGF3/FGF4/FGF 19, ou les patientes atteintes d'un cancer du sein sans aucune amplification des gènes cités précédemment. The efficacy of the combination of 6 - ({7 - [(1-amino cyclopiOpyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide was observed in both cycles of treatment and fulvestrant is assessed via evaluation of tumor response using the RECIST version 1.1 criterion (CT-scan or JRM). The acceptability profile is also evaluated (hematologic, cardiac, renal and hepatic toxicities). Molecular screening is also performed to determine breast cancer patients with FGFR1 gene amplification and / or CCND 1 / FGF3 / FGF4 / FGF 19 genes, or breast cancer patients without breast cancer. no amplification of the genes mentioned above.
Les résultats montrent que l'utilisation du 6-({7-[(l -aminocyclopropyl)méthoxy]-6- méthoxyquinoléin-4-yl} oxy)-N-méthylnaphtalène-l -carboxamide en association avec le fulvestrant est encourageante pour le traitement du cancer, et plus particulièrement pour le traitement du cancer du sein métastatique ER+/HER2-, The results show that the use of 6 - ({7 - [(1-aminocyclopropyl) methoxy] -6-methoxyquinolin-4-yl} oxy) -N-methylnaphthalene-1-carboxamide in combination with fulvestrant is encouraging for treatment of cancer, and more particularly for the treatment of ER + / HER2- metastatic breast cancer,
Claims
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| FR1357936A FR3009497B1 (en) | 2013-08-09 | 2013-08-09 | NOVEL ASSOCIATION BETWEEN 6 - ({7 - [(1-AMINOCYCLOPROPYL) METHOXY] -6-METHOXYQUINOLIN-4-YL} OXY) -N-METHYLNAPHTALENE-1-CARBOXAMIDE AND AN ANTI-OESTROGEN IN BREAST CANCER |
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|---|---|---|---|---|
| CN110483393A (en) * | 2018-05-14 | 2019-11-22 | 上海海和药物研究开发有限公司 | The crystal form of Delitinib |
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| WO2008112408A1 (en) * | 2007-03-14 | 2008-09-18 | Advenchen Laboratories, Llc | Spiro substituted compounds as angiogenesis inhibitors |
| WO2009039700A1 (en) * | 2007-09-24 | 2009-04-02 | Xi'an Libang Pharmaceutical Co., Ltd. | Process for the manufacture of 7-alpha-[9-(4,4,5,5,5-penta fluoropentvlsulphinvl) nonvllestra-l,3,5-(10)- triene-3,17-beta-diol |
| WO2011072244A1 (en) * | 2009-12-10 | 2011-06-16 | Mount Sinai School Of Medicine Of New York University | Method of treatment of breast cancer with tamoxifen |
-
2013
- 2013-08-09 FR FR1357936A patent/FR3009497B1/en not_active Expired - Fee Related
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2014
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| WO2008112408A1 (en) * | 2007-03-14 | 2008-09-18 | Advenchen Laboratories, Llc | Spiro substituted compounds as angiogenesis inhibitors |
| WO2009039700A1 (en) * | 2007-09-24 | 2009-04-02 | Xi'an Libang Pharmaceutical Co., Ltd. | Process for the manufacture of 7-alpha-[9-(4,4,5,5,5-penta fluoropentvlsulphinvl) nonvllestra-l,3,5-(10)- triene-3,17-beta-diol |
| WO2011072244A1 (en) * | 2009-12-10 | 2011-06-16 | Mount Sinai School Of Medicine Of New York University | Method of treatment of breast cancer with tamoxifen |
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Cited By (1)
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| CN110483393A (en) * | 2018-05-14 | 2019-11-22 | 上海海和药物研究开发有限公司 | The crystal form of Delitinib |
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| FR3009497B1 (en) | 2015-08-07 |
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